Immunization against specific disease promoting hormones may be useful in the treatment and prevention of certain diseases and cancers. Such immunological approaches to the treatment and prevention of gastric and duodenal ulcer disease and gastro-intestinal cancer are disclosed in co-assigned U.S. Pat. No. 5,023,077 and PCT application WO 90/08774. According to these immunological approaches, specific antibodies neutralize the biological activity of disease promoting gastrointestinal peptide hormones. The antibodies are specific for a particular hormone, and one or more hormones can be selectively targeted to treat a particular disease. For example, human gastrointestinal hormone gastrin 17 ("hG17") is involved in gastrointestinal disease processes including gastro-esophageal reflux disease, gastric and duodenal ulceration and cancer. Specific anti-hG17 antibodies which neutralize the action of hG17 can therefore be used to treat diseases in which hG17 is involved. The anti-hormone antibodies can be administered to the patient (i.e., passive immunization) or they can be induced in the patient by active immunization.
Active immunization against gastrointestinal peptide hormones is accomplished by administering to the patient an immunogen that contains chemical structures that induce antibodies which bind to the targeted hormone. Such chemical structures are defined as immunomimics of the targeted hormone, and can be composed of any molecule that immunologically crossreacts with the targeted hormones. Immunomimics may inherently possess the capacity to induce antibodies, e.g., they may be immunogenic, however, frequently, immunomimics are not inherently immunogenic, and they must be linked to immunogenic carrier molecules to be rendered immunogenic.
The immunogens of U.S. Pat. No. 5,023,077, the disclosure of which is hereby incorporated by reference in its entirety, and of the present invention comprise an immunogenic carder, such as diphtheria toxoid ("DT"), to which is linked peptides that are immunomimics of hG17's amino terminal epitope. The peptides are composed of two functional regions: an immunomimic and a spacer. The function of the immunomimic is to induce antibodies that bind to the targeted hormone. Any chemical structure that immunologically crossreacts with the unique amino terminal epitope of hG17 can serve as the immunomimic. In a preferred embodiment the immunomimic peptide is a fragment of hG17 which contains within it the amino terminal epitope of hG17. The spacer element of the peptide serves as a link through which the immunomimic is attached to the carder. The spacer can also affect the immune response against the immunomimic.
We have determined that certain specific peptide immunomics of hG17 coupled to a specific spacer peptide are improved immunogens which result in an unexpectedly improved immune response. One specific improved immunogen against the amino terminal epitope of hG17, comprises a peptide identified as SEQ ID NO: 1 in the Sequence Listing, of the sequence: pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Ser-Ser-Pro-Pro-Pro-Pro-Cys coupled to an immunogenic carrier such as diphtheria toxoid, tetanus toxoid, keyhole limpet hemocyanin, etc. Diphtheria toxoid is the preferred immunogenic carrier in this ("hG17(1-9)-Ser9") peptide, the sequence identified as SEQ ID NO.: 2 in the Sequence Listing is pGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu- comprises the immunomimic of hG17. The remainder of the peptide's sequence, identified as SEQ ID NO.: 3 in the Sequence Listing, is Ser-Ser-Pro-Pro-Pro-Pro-Cys, constitutes the spacer.
Typically, the induction of effective antibody responses by immunization with immunomimic-carrier complexes requires two or more administrations of immunogen and takes several weeks or months for the antibody titers to rise to the desired levels. The improved immunogens of the present invention induce effective levels of antibody shortly after a single administration of immunogen.